chr18-31093631-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_024422.6(DSC2):c.82G>T(p.Ala28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,583,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 0.288

Publications

3 publications found

Variant links:

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

DSC2 Gene-Disease associations (from GenCC):

familial isolated arrhythmogenic right ventricular dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 11
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07590294).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000867 (13/149956) while in subpopulation AFR AF = 0.000295 (12/40628). AF 95% confidence interval is 0.00017. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DSC2	NM_024422.6	MANE Select	c.82G>T	p.Ala28Ser	missense	Exon 2 of 16	NP_077740.1
DSC2	NM_004949.5		c.82G>T	p.Ala28Ser	missense	Exon 2 of 17	NP_004940.1
DSC2	NM_001406506.1		c.-348G>T		5_prime_UTR	Exon 2 of 16	NP_001393435.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DSC2	ENST00000280904.11	TSL:1 MANE Select	c.82G>T	p.Ala28Ser	missense	Exon 2 of 16	ENSP00000280904.6
DSC2	ENST00000251081.8	TSL:1	c.82G>T	p.Ala28Ser	missense	Exon 2 of 17	ENSP00000251081.6
DSC2	ENST00000713707.1		c.82G>T	p.Ala28Ser	missense	Exon 2 of 16	ENSP00000519010.1

Frequencies

GnomAD3 genomes

AF:

0.0000867

AC:

AN:

149956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000488

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249794

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000126

AC:

AN:

1433380

Hom.:

Cov.:

AF XY:

0.00000981

AC XY:

AN XY:

713340

show subpopulations

African (AFR)

AF:

0.000426

AC:

AN:

32862

American (AMR)

AF:

0.0000227

AC:

AN:

44028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25116

East Asian (EAS)

AF:

0.00

AC:

AN:

38602

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1093736

Other (OTH)

AF:

0.0000170

AC:

AN:

58722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000867

AC:

AN:

149956

Hom.:

Cov.:

AF XY:

0.0000548

AC XY:

AN XY:

73024

show subpopulations

African (AFR)

AF:

0.000295

AC:

AN:

40628

American (AMR)

AF:

0.00

AC:

AN:

15018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67670

Other (OTH)

AF:

0.000488

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000276

Hom.:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Arrhythmogenic right ventricular dysplasia 11 (1)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Familial isolated arrhythmogenic right ventricular dysplasia (1)

not specified (1)

Primary familial dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.0

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.060

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.49

M_CAP

Benign

0.040

MetaRNN

Benign

0.076

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.29

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.80

REVEL

Benign

0.051

Sift

Benign

0.58

Sift4G

Benign

0.41

Polyphen

0.024

Vest4

0.19

MVP

0.46

MPC

0.086

ClinPred

0.014

GERP RS

1.3

Varity_R

0.036

gMVP

0.44

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over